Monique B. Perry

Phenotype and course of Hutchinson-Gilford progeria syndrome

BACKGROUND Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription. METHODS We enrolled 15 children between 1 and 17 years of age, representing nearly half of the worlds known patients with Hutchinson-Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006. RESULTS Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle-brachial indexes, and adventitial thickening. CONCLUSIONS Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393.)

A 3-year randomized therapeutic trial of nitisinone in alkaptonuria.

Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3 years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis.

Ultrasound, magnetic resonance imaging, and posterior tibialis dysfunction.

The authors studied posterior tibialis tendons in 31 subjects with posterior tibialis tendon pain to compare clinical findings with those of magnetic resonance imaging and ultrasound images. All subjects received clinical, ultrasound, and magnetic resonance imaging examinations using T1-weighted, T2-weighted, and enhanced magnetic resonance imaging, and high resolution ultrasound using power Doppler. Forty-four tendons in 25 women and six men with a mean age 43.3 years (range, 20–73 years) were studied. Magnetic resonance imaging tendon and peritendon enhancement are associated statistically with increasing pain intensity on resistance to testing. Ultrasound tendon and peritendon flow were associated with increasing pain intensity on resistance to testing. There is no statistically significant association between magnetic resonance imaging inhomogeneity and pain intensity on resistance to testing. Clinical and ultrasound examinations positively identify peritendinitis and tendonitis but not inhomogeneity (partial tear) of the posterior tibialis tendon. The magnetic resonance imaging is a more sensitive test for posterior tibialis tendon tear than either clinical or ultrasound evaluation.

Digital Stereophotogrammetry as a New Technique to Quantify Truncal Deformity: A Pilot Study in Persons with Osteogenesis Imperfecta

The objective of this pilot study was to determine the usability of stereophotogrammetry (SP) as a noninvasive technique for obtaining linear measures and anatomical data of the torso in people with osteogenesis imperfecta in comparison with clinical observations. Ten participants were recruited from subjects enrolled in ongoing institutional review board-approved osteogenesis imperfecta protocols at the National Institute of Child Health and Human Development. Using a Gulick tape measure, anthropometer, and the SP system proprietary software, linear measurements of the torso were taken. In addition, the presence or absence of specific torso deformities was documented from both clinical observation and evaluation of SP images. Measurements of torso diameter and circumference by SP demonstrated strong agreement with the manual measurements (intraclass correlation coefficient = 0.995 and 0.964, respectively). Substantial and statistically significant agreement was present between SP image evaluation and clinical observation for pectus carinatum (&kgr; = 0.52 ± 0.23) and thoracic scoliosis (&kgr; = 0.72 ± 0.12). The kappa values between clinical observation and SP evaluations of other torso deformities were not significant. The strong correlations and P values determined by this study demonstrate the potential value of SP in studying persons with truncal deformities. However, the weak agreement between SP and some clinical observations suggests that further development of SP image analysis tools is required before SP can be used as a standard method of diagnosis or assessment of treatment success.

Poster 1: Physical and functional performance in alkaptonuria1

Abstract Objectives: To describe the physical and functional performance in patients with alkaptonuria and to determine if particular impairments correlate with functional performance. Design: Descriptive prospective research study. Setting: Biomedical research facility. Participants: 53 subjects with alkaptonuria (31 men, 22 women; mean age, 43.6y; range, 10–80y). Interventions: Functional questionnaires, history, physical exam (including Schober test), and plain film radiographs. Main Outcome Measures: The Human Activity Profile (HAP), a measure of physical activity, the Health Assessment Questionnaire (HAQ), a measure of activities of daily living and health status, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the Fatigue Assessment Instrument (FAI). Results: The adjusted physical activity score (AAS) in the HAP identified 12 subjects who had normal activity, and 14 with mildly, 17 with moderately, and 10 with severely limited activities. The HAQ described 14 subjects with no functional limitation, and 17 with mild, 17 with moderate, and 4 with severe limitations. The FAI identified 27 subjects with normal levels of fatigue and 26 with abnormally increased fatigue. The Physical Component Summary (PCS) score of the SF-36 identified 44 subjects with lower and 9 with higher health scores compared with a normal population. The Mental Component Summary scores of the SF-36 identified 19 subjects below and 34 above the norm. The PCS correlated significantly with total joint abnormal range of motion ( P =.0003), kyphosis ( P =.0011), Schober test (spine flexion) ( P P P =.0336), shoulder severity ( P =.0374), and total spine severity scores ( P =.0023). The AAS correlated significantly with the Schober test ( P =.0213), age ( P =.0225), radiographic total large joint severity score ( P =.0315), total spine severity ( P =.0097), and thoracic ( P =.0449) and lumbar spine severity ( P =.0020). Conclusion: Patients with alkaptonuria have significant impairment, functional limitation, and disability (HAQ; SF-36) compared with a normal population. Disability (SF-36) and functional limitation (HAP) increase with age and clinical and radiographic measures of joint severity in large joints and spine.

Poster 12 Functional Limitations and Disabilities in Alkaptonuria in a 3-Year Treatment Trial With Nitisinone

exam, was otherwise normal. He was subsequently sent for radiographs of the pelvis and bilateral (B/L) hips which revealed advanced degenerative joint disease (DJD). On AP view, radiographic measurements of the neck shaft angles were found to be greater than 142°, while lateral radiographs showed an anteverted neck in relation to the femoral shaft. Setting: Outpatient physiatry office. Results or Clinical Course: The radiographic findings, in combination with clinical presentation, helped confirm the diagnosis of B/L pistol grip hip deformity (PGD). Such deformity led to severe progressive DJD, which limited both ROM and the performance of activities of daily living. As a result, the patient underwent B/L total hip arthroplasty (THA) without complication. Discussion: PGD is a pre-arthritic condition with a greater prevalence in adults who are younger than 50 years old and are very physically active. Such patients presenting with groin pain and decreased hip ROM should be evaluated for PGD. The triad of Cam type anterior femoral acetabular impingement, DJD, and a femoral neck-shaft angle 140° or 115° with radiographic evidence of an abnormally shaped femoral head is suggestive of PGD. Significant benefit may arise from early recognition and orthopedic evaluation in terms of diagnosis and treatment. Conclusions: PGD left untreated is progressive and ultimately leads to THA. With early recognition, there is potential for successful treatment via arthroscopy. It is therefore imperative that the rehabilitation physician be familiar with this condition so that such a condition does not go unnoticed.

Poster 231: Impairments, Functional Limitations, and Disability in Adults With Sickle Cell Anemia

(VIT) and Human Activity Profile maximal activity (MAS). Results: There were 8 men and 14 women, 11 each with HCV and NAFLD. Mean age 52 years, BMI 33, resting heart rate 77 bpm, O2 saturation 98%. Mean FSS score was 4.5 (fatigued). Grip strength below norm. VIT was normal. Post 6MW, mean heart rate increased to 92 bpm (52% max) and O2 saturation dropped to 97%. The presence of the MS was associated with a slow 6MW distance, walking speed, and change in heart rate (r -0.38 to 0.41, P .095-0.07). AST levels significantly correlated with self-reports of fatigue (FSS) and MAS (r 0.65, P .0024; and r 0.48, P .038), respectively. Analyzing NAFLD and HCV groups separately revealed only subjects with NAFLD and metabolic syndrome had a significant correlation between walk distance and rate (r -0.78, P .01). Correlation between abnormal liver enzymes and FSS was (P .07) in each group. Conclusions: Subjects with liver disease are deconditioned, perform at 52% of predicted heart rate maximum, have low grip strength, walk more slowly, report less physical activity and a higher level of fatigue than a normed sample. Abnormal liver function correlates with self-reports of fatigue and activity, but not with objective measures of performance. The presence of the MS correlated with performance measures, while BMI did not. This suggests that metabolic status, energy production and utilization may be important for performance (rate and distance walked); and elevated enzymes (inflammation) associated with fatigue, in this population.

Poster 236: Relationships of Body Mass Index with Impairments, Functional Limitations and Disability

made. No biopsy was performed. The patient was treated with intravenous corticosteroids with some improvement in her hemiparesis, but continued to have impairment of mobility and self-cares. Subsequently, she was transferred to acute inpatient rehabilitation, where she made significant functional improvement with physical and occupational therapy. The patient’s anxiety was initially a barrier to therapy participation. Fortunately, her motivation improved considerably after several sessions with our rehabilitation psychologist. Obesity was also contributing to her impaired function, so she was referred for an endocrinology and nutrition evaluation. After 1 month of rehabilitation, she had regained her ability to ambulate safely without a gait aid and perform her self-cares independently. Discussion: Tumefactive MS lesions have atypical imaging features, including size 2 cm, mass effect and ring enhancement. Like other forms of MS, it is more common in females and usually affects individuals in their 3rd or 4th decade of life. Unlike the patient in this case, this rare form of MS usually presents with a combination of motor, sensory, and cognitive symptoms. In addition to the interesting presentation and atypical imaging, this case highlights the important role of inpatient rehabilitation in a patient with acute tumefactive MS. It also illustrates the importance of considering comorbidities, such as obesity and anxiety disorders, when creating a rehabilitation plan. Conclusions: Patients recovering from acute tumefactive MS may benefit significantly from inpatient rehabilitation.